EVEREST Data Use of Otsuka America Pharmaceutical, Inc.'s Investigational Novel Treatment, Tolvaptan, Published in Journal of the American Medical Association and Featured in ACC's Late Breaking Clinical Trials 3/26/2007 11:00:52 AM

PRINCETON, N.J., March 25 /PRNewswire/ -- Once-daily dosing with Otsuka's investigational oral medication tolvaptan, a vasopressin receptor antagonist, was associated with improvements in signs and symptoms of acutely decompensated heart failure (ADHF) in hospitalized patients receiving conventional care, without an adverse effect on their long-term survival versus placebo.(1) These data are from the short- and long-term analyses of the international landmark trial Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) published in the March 28 issue of the Journal of the American Medical Association (JAMA). These data were presented at the American College of Cardiology's 56th Annual Scientific Sessions (ACC).

The phase 3 EVEREST trial, involving a total of 4,133 ADHF patients, represents three studies: a long-term outcomes trial evaluating patients after their discharge for a minimum of 60 days of treatment, and two identical, embedded short-term pivotal studies that examined tolvaptan compared to placebo over seven days of inpatient care or discharge, whichever came first.(1,2)

Data from the two short-term studies documented that tolvaptan treatment yielded significantly greater improvements than placebo based on the primary endpoint (study A: p less than 0.001 and study B: p less than 0.001), which was the composite score of changes in patient-assessed global clinical status and changes in body weight at day seven or discharge.(1) Long-term tolvaptan use did not differ from placebo on either of the study's two primary endpoints: deaths from all causes (p equal to 0.68) or from the combined endpoint of cardiovascular (CV) deaths or subsequent hospitalization for worsening HF (p equal to 0.55).(2)

"Tolvaptan exhibited short-term symptomatic benefits in patients hospitalized with worsening heart failure,"(2) said investigator Marvin A. Konstam, M.D., chief of the Division of Cardiology at the Tufts-New England Medical Center, and professor of Medicine at Tufts University School of Medicine, Boston, Mass. Konstam presented the short- and long-term EVEREST data analyses during a late-breaker session Sunday, March 25 at the ACC. "In the long-term trial, tolvaptan neither statistically improved nor worsened survival relative to placebo. The EVEREST data suggest that tolvaptan may be a potential therapy for patients with heart failure."

Tolvaptan is a novel, investigational small molecule designed to be an antagonist of the vasopressin V2 receptor, which plays a role in the kidney's regulation of fluid excretion. The majority of patients hospitalized for ADHF, the worsening of chronic HF that affects 1 million U.S. residents annually,(3) have edema or excess body fluid, which is treated with diuretics to excrete the fluid. In contrast to diuretics, tolvaptan is designed to promote aquaresis, the excretion of electrolyte-free water.(1) Otsuka Pharmaceutical Co., Ltd. (Japan) and Otsuka Pharmaceutical Development & Commercialization, Inc., are developing tolvaptan, which has the potential to be the first available oral vasopressin receptor antagonist.(4,5)

Short-Term Studies: Pre-Specified Secondary Endpoints

In the two short-term studies, reductions in average body weight at day seven or discharge were statistically significantly different between the tolvaptan group versus the placebo group, 3.35 kilograms (kg) and 2.73 kg, respectively, in study A (p less than 0.001) and 3.77 kg and 2.79 kg, respectively, in study B (p less than 0.001). In addition, the use of tolvaptan significantly reduced patients' body weight as early as on the first day of treatment in both short-term studies (p less than 0.001).(1) There was no significant difference between the treatment groups in improvement in patient-assessed global clinical status at day 7 or discharge, if earlier; however the changes were numerically in favor of tolvaptan.

In each short-term study, significantly more patients in the tolvaptan groups reported improvements in dyspnea (difficult breathing) on the first inpatient day compared with the placebo groups (p less than 0.001 in both study A and study B). Significantly more patients in the tolvaptan group had improvements in investigator-assessed pedal edema at inpatient day seven or discharge in study B (p equal to 0.020), while the difference between groups in study A did not reach statistical significance (p equal to 0.070).(1)

Long-Term Trial: Pre-Specified Secondary Endpoints

The secondary endpoints of the composite of cardiovascular death or cardiovascular hospitalization, the incidence of cardiovascular mortality, and the incidence of clinical worsening of heart failure did not differ between the two treatment groups. A larger number of cardiovascular hospitalizations were adjudicated as due to myocardial infarction in the placebo group (n equal to 42) than in the tolvaptan group (n equal to 25) and a larger number were adjudicated as due to stroke in the tolvaptan group (n equal to 45) than in the placebo group (n equal to 24).(2)

The long-term tolvaptan data were consistent with those reported in the short-term clinical studies. Specifically, long-term tolvaptan treatment significantly reduced participants' body weight at day one (p less than 0.001) compared to placebo and the difference in body weight numerically favored tolvaptan through week 56. The long-term trial also documented that tolvaptan patients who enrolled with hyponatremia (serum sodium less than 134 mEq/L) exhibited significantly greater corrections in serum sodium at day seven or discharge, if earlier, (p less than 0.001) and the effect was maintained through 40 weeks of treatment.(2)

"The EVEREST data suggest that the mechanism of action of tolvaptan may represent a new therapeutic strategy that could provide symptomatic improvement for short-term care of hospitalized heart failure patients,"(1) said Cesare Orlandi, M.D., vice president of Clinical Development at Otsuka Pharmaceutical Development & Commercialization, Inc.

Safety Data

Common adverse events associated with tolvaptan were dry mouth and thirst, which are consistent with the pharmacologic effects of the drug.(1,2) In the EVEREST trial, adverse events resulting in study drug discontinuation occurred in 6.5 percent of tolvaptan patients and 5.5 percent of placebo patients. Among these, only thirst occurred significantly more frequently with tolvaptan (n equal to 7) vs. placebo (n equal to 0); (p equal to 0.02). Dry mouth resulted in discontinuation in 4 tolvaptan patients vs. 0 placebo patients (p equal to 0.12).

Hypernatremia occurred in 1.7 percent of tolvaptan patients, compared to 0.5 percent of placebo patients. The incidence of kidney failure and low blood pressure were comparable in the two groups. Tolvaptan-treated patients showed no differences from placebo-treated patients with regards to heart rate and blood pressure. In addition, tolvaptan demonstrated no deleterious effects on renal function relative to placebo in these patients.(2)

About EVEREST

EVEREST is a landmark, prospective, international, multicenter, randomized, double-blind, placebo-controlled trial conducted at 432 sites in North America, South America and Europe between 2003 and 2006. EVEREST investigators randomized patients with worsening congestive heart failure and who had a left ventricular ejection fraction (LVEF) of 40 percent or less within 48 hours of their hospitalization to receive either 30 milligrams (mg) tolvaptan once-daily or a placebo until the end of the long-term outcome trial. Additionally, treating physicians could choose conventional therapies for their patients, including diuretics, digoxin, ACE inhibitors, angiotensin II receptor blockers, aldosterone blockers, beta-blockers, nitrates, nesiritide and/or hydralazine.(1)

"EVEREST adds to the collection of data on tolvaptan and its potential uses," said Kazumichi Kobayashi, Chairman & CEO of Otsuka Pharmaceutical Development & Commercialization, Inc. "Tolvaptan, as one of our most advanced candidate therapies, exemplifies the successful application of Otsuka's expertise in new drug research and development."

About Heart Failure

More than 14 million people in Europe(6) and five million U.S. residents(7) have heart failure (HF), a serious chronic condition in which the heart cannot effectively pump blood. The direct and indirect U.S. health care expenses related to HF tally about $28 billion, ACC estimates.(5) The majority of patients hospitalized for ADHF, the worsening of chronic HF that affects 1 million US residents annually, have edema or excess body fluid.(3)

About Otsuka Pharmaceutical Development & Commercialization, Inc.

Otsuka Pharmaceutical Development and Commercialization, Inc. is involved in conducting all phases of clinical research and development of innovative healthcare products to address unmet medical needs. OPDC is well established in the scientific community as a globally focused organization that plays a leadership role in the research and development of Otsuka's ethical healthcare products. The Company is dedicated to the improvement of the quality of human life and health of patients around the world with a strong commitment to research and development in the areas of cardiovascular, neuroscience, renal and respiratory diseases, as well as cancer and ophthalmic disorders. OPDC is part of the Otsuka Pharmaceutical Group, which is comprised of 87 companies and approximately 27,000 people around the world. With 44 consolidated subsidiaries, Otsuka earned US $6.8 billion in consolidated annual revenues in fiscal 2005. For additional information, visit www.otsuka.com.